Three-component synthesis of 3-(diarylmethyl)indoles using Fe(ClO4)3/SiO2 as catalyst

Article abstract of DOI:10.1134/S107042801703023X

Three-component reaction of indole, aromatic aldehyde, and N,N-dimethyl aniline in the presence of silica-supported Fe(ClO₄)₃ as catalyst afforded the corresponding 3-[aryl(4-dimethylaminophenyl)methyl]-indoles in excellent yields un

Full text of DOI:10.1134/S107042801703023X

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2017, Vol. 53, No. 3, pp. 454–458. © Pleiades Publishing, Ltd., 2017.
Three-Component Synthesis of 3-(Diarylmethyl)indoles
Using Fe(ClO4)3/SiO2 as Catalyst1
E. Najafi and F. K. Behbahani*
Department of Chemistry, Karaj Branch, Islamic Azad University, Karaj, Iran 31485313
*e-mail: Farahnazkargar@yahoo.com
Received October 8, 2016
Abstract—Three-component reaction of indole, aromatic aldehyde, and N,N-dimethyl aniline in the presence
of silica-supported Fe(ClO4)3 as catalyst afforded the corresponding 3-[aryl(4-dimethylaminophenyl)methyl]-
indoles in excellent yields under mild conditions. The proposed protocol offers some remarkable advantages
such as the use of a solid catalyst and simple workup procedure.
DOI: 10.1134/S107042801703023X
Indoles are important structural units in many
natural products, and their derivatives are known to
possess various biological properties [1] such as
antibacterial, antioxidant, and insecticidal activities.
Some indole derivatives have been used as antibiotics
and pharmaceuticals [2]. Among indole derivatives,
bisindolylalkanes, 3-alkylindoles, and 3-(diarylmethyl)-
indoles constitute an important class of bioactive
metabolites. They can be synthesized using Lewis
acids as catalysis [3–8], e.g., FeCl3 [11], ZnCl2 [12],
CuCl2 [13], and Fe3O4–OSO3H [14]. Although the
synthesis of 3-alkylindoles has been studied exten-
sively, more practical mild procedures for the synthesis
of other unsymmetrical indole derivatives are still
highly desirable.
Following our previous research on the use of eco-
friendly catalytic protocols for the synthesis of hetero-
cyclic compounds [9–10], herein we present a new,
mild, and green procedure for the preparation of 3-(di-
arylmethyl)indoles from N,N-dimethylaniline (1),
aromatic aldehydes 2, and indole in the presence of
Fe(ClO4)3/SiO2 in refluxing acetonitrile (Scheme 1).
Initially, different solvents were tried in the model
reaction of benzaldehyde (2a) with N,N-dimethylani-
line and indole. The results showed that the catalyst
worked more efficiently in acetonitrile (Table 1).
Scheme 1.
CHO
We also studied the effect of the amount of
Fe(ClO4)3/SiO2 on the reaction in acetonitrile. It was
found that the amount of the catalyst is crucial for
achieving the desired yield. The best result was ob-
tained using 0.2 g of Fe(ClO4)3/SiO2 (Table 2).
NMe2
+
+
N
R
H
1
2a–2i
Table 1. Reaction of N,N-dimethylaniline (1) with benzalde-
hyde (2a) and indole in the presence of Fe(ClO4)3/SiO2 in
different solventsa
Me2N
Fe(ClO4)3/SiO2
MeCN, reflux
Solvent
Temperature, °C
Yield of 3a,b %
R
None
100
85
80
CH2Cl2
CHCl3
MeCN
H2O
Reflux
Reflux
Reflux
Reflux
80
N
H
92
3a–3i
<10<
R = H (a), 4-Me (b), 4-Cl (c), 2-Cl (d), O2N (e),
3,4-(MeO)2 (f), 3-HO (g), 4-HO (h), 4-MeO (i).
a
Reaction time 2 h; hereinafter, 1.0 mmol of each reactant, 0.2 g
of Fe(ClO4)3/SiO2, and 1.0 mL of the solvent were used.
Hereinafter, isolated yield is given.
1
b
The text was submitted by the authors in English.
454

THREE-COMPONENT SYNTHESIS OF 3-(DIARYLMETHYL)INDOLES
455
Table 2. Effect of the catalyst amount in the synthesis of
4-[(1H-indol-3-yl)(phenyl)methyl]-N,N-dimethylaniline (3a)
To examine the scope and generality of this proto-
col, we used different substituted benzaldehydes. The
data in Table 3 show that benzaldehydes having both
electron-donating and electron-withdrawing groups
afforded the desired products in high yields.
A plausible mechanism of the reaction is shown in
Scheme 2. Electrophilic substitution in N,N-dimethyl-
aniline (1) with Fe(ClO4)3/SiO2-activated benzalde-
hyde A gives intermediate B which loses
(OH)Fe(ClO4)3/SiO2 due to “push–pull” effect of
nonbonding electrons of N,N-dimethlyaniline. Cationic
intermediate C thus formed adds to C3 of indole,
yielding 3H-indolium intermediate D, and proton
abstraction from the latter leads to final 3-substituted
indole 3.
Fe(ClO4)3/SiO2, g Reaction time, h
Yield, %
No catalyst
4.0
2.0
2.0
2.0
10
70
90
92
0.3
0.5
0.2
EXPERIMENTAL
The melting points were measured by the capillary
method with an Electrothermal 9200 apparatus. The IR
spectra were recorded in KBr on a Perkin Elmer FT-IR
1
spectrometer in the range 4000–400 cm–1. The H and
13C NMR spectra were obtained on a Bruker DRX-300
To show advantages of using Fe(ClO4)3/SiO2 as
a solid catalyst in the synthesis of 4-[(1H-indol-3-yl)-
(phenyl)methyl]-N,N-dimethylaniline, our protocol
was compared with previously reported methods
(Table 4). It is evident that the proposed procedure is
advantageous regarding the yield and reaction time
which are very important factors for large-scale
processes, especially in combination with easy separa-
tion and reusability of the catalyst.
1
instrument (300 MHz for H and 75 MHz for 13C)
using CDCl3 as solvent; the chemical shifts were
measured relative to tetramethylsilane as internal
standard. The mass spectra were taken on an Agilent
5973 Network Mass Selective Detector.
Analytical TLC of all reactions was performed on
silica gel 60 F-254 precoated plates (Merck). Elemen-
tal analyses of the newly synthesized compounds were
Scheme 2.
Me2N
H
O
:
NMe2
H
O
Fe(ClO4)3/SiO2
CHO
Fe(ClO4)3/SiO2
Fe(ClO4)3/SiO2
R
R
R
2
A
B
H
N
H
O
H
N
Fe(ClO4)3/SiO2
H
Fe(OH)(ClO4)3/SiO2
–Fe(OH)(ClO4)3/SiO2
Me2N
Me2N
R
R
C
D
NH
–Fe(ClO4)3/SiO2
–H2O
R
Me2N
3
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NAJAFI, BEHBAHANI
456
Table 3. Synthesis of 3-(diarylmethyl)indoles 3a–3i in the presence of Fe(ClO4)3/SiO2
mp, °C
Aldehyde no.
R
Product no.
Reaction time, h
Yield, %
found
reported [4]
2a
2b
2c
2d
2e
2f
H
3a
3b
3c
3d
3e
3f
158–160
160–163
129–130
150–152
130–132
138–140
150–152
142–144
145–150
161–162
2.0
2.0
2.0
2.0
3.0
2.0
2.0
2.0
3.0
92
90
95
95
90
95
90
90
90
4-Me
164–165
4-Cl
130–132
2-Cl
152–153
3-O2N
3,4-(MeO)2
3-HO
–
–
–
–
–
2g
2h
2i
3g
3h
3i
4-HO
4-MeO
Table 4. Synthesis of 4-[(1H-indol-3-yl)(phenyl)methyl]-N,N-dimethylaniline (3a) in the presence of different catalysts
Catalyst, mol % (g)
Solvent
Temperature, °C
Reaction time, h
Yield, %
Reference
FeCl3, 10
1,2-Dichloroethane
1,2-Dichloroethane
1,2-Dichloroethane
1,2-Dichloroethane
1,2-Dichloroethane
1,2-Dichloroethane
Toluene
100
100
24
24
65
15
18
31
26
38
76
65
95
[11]
[11]
Fe(NO3)3·9H2O, 10
Fe(SO4)3·7H2O, 10
Fe2(SO4)4, 10
Fe(acac)3, 10
100
24
[11]
100
24
[11]
100
24
[11]
FeCl2, 10
100
24
[11]
ZnCl2, 100
100
0.05.0
11
[12]
PMA-SiO2, 15
Fe(ClO4)3/SiO2 (0.2)
PEG-400
110
[15]
MeCN
Reflux
2.0
This work
obtained using a Vario EL III analyzer and were in
a good agreement with the calculated values. All
starting materials were purchased from Merck and
Acros Organics.
cooled, 25 ml of CH2Cl2 was added, and the catalyst
was separated by filtration. The filtrate was evaporated
under reduced pressure, and the crude product was
purified by recrystallization from ethanol. The catalyst
is reusable and could be recycled for five runs without
appreciable decrease in catalytic activity. The yields
and melting points of 3a–3i are given in Table 3.
Silica-supported iron(III) perchlorate. A solution
of 1.0 g of Fe(ClO4)3 in 10 ml of ethanol was added to
a suspension of 10 g of silica gel (Kieselgel 40, 70–
230 mesh; Merck) in 30 ml of ethanol. The mixture
was stirred for 30 min, and the solvent was evaporated
under reduced pressure. The resulting brown powder
was further dried in a vacuum drying cabinet at 60°C
under reduced pressure (20 mm) [16].
4-[(1H-Indol-3-yl)(phenyl)methyl]-N,N-dimethyl-
aniline (3a). IR spectrum, ν, cm–1: 3400 (NH), 1676
(C=N), 1614, 1518, 1492, 1455, 1417 (C=C), 1223,
1
1124 (C–N). H NMR spectrum (300 MHz, δ, ppm:
2.93 s (6H, NCH3), 5.59 s (1H, CH), 6.80 s (1H, 2-H),
7.30–6.80 m (12H, Harom), 7.92 s (1H, Harom), 9.88 s
(1H, NH). 13C NMR spectrum, δC, ppm: 40.67 (NCH3),
54.66 (CH), 111.05, 114.32, 116.22, 118.84, 122.09,
127.33, 130.45, 132.12, 134.30, 144.08, 148.11. Mass
spectrum: m/z 326.43 [M]+.
General procedure for the synthesis of 3-(diaryl-
methyl)indoles 3a–3i. To a mixture of aromatic
aldehyde (1.0 mmol), N,N-dimethylaniline (1.0 mmol),
and indole (1.0 mmol) in acetonitrile (1.0 ml) 0.2 g of
Fe(ClO4)3/SiO2 was added, and the reaction mixture
was refluxed with stirring for appropriate time. After
completion of the reaction (TLC), the mixture was
4-[(1H-Indol-3-yl)(4-methylphenyl)methyl]-N,N-
dimethylaniline (3b). IR spectrum, ν, cm–1: 3411
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 53 No. 3 2017

THREE-COMPONENT SYNTHESIS OF 3-(DIARYLMETHYL)INDOLES
457
(NH), 1658 (C=N), 1610, 1510, 1483, 1456, 1416
(C=C), 1217, 1092 (C–N). 1H NMR spectrum, δ, ppm:
2.23 s (3H, CH3), 2.92 s (6H, NCH3), 5.56 s (1H, CH),
6.64 s (1H, 2-H), 7.24–6.8 m (11H, Harom), 7.90 s
(1H, Harom), 9.87 s (1H, NH). 13C NMR spectrum,
δC, ppm: 25 (CH3), 40.45 (NCH3), 54.45 (CH), 111.31,
114.02, 116.31, 118.11, 122.80, 127.14, 130.33,
132.20, 135.28, 140.12, 147.09. Mass spectrum:
m/z 340.46 [M]+.
[M]+, 116 (100). Found, %: C 77.56; H 6.58; N 7.11.
C25H26N2O2. Calculated, %: C 77.69; H 6.78; N 7.25.
4-[(3-Hydroxyphenyl)(1H-indol-3-yl)methyl]-
N,N-dimethylaniline (3g). IR spectrum, ν, cm–1: 3380
(NH, OH), 1679 (C=N), 1587, 1512, 1456, 1422
(C=C), 1268, 1136 (C–N). 1H NMR spectrum, δ, ppm:
2.88 s (6H, NCH3), 5.52 s (1H, CH), 6.56 s (1H, 2-H),
7.33–6.67 m (12H, Harom), 7.92 s (1H, OH), 9.80 s (1H,
NH). 13C NMR spectrum, δC, ppm: 40.64 (NCH3),
55.32 (CH), 114.00, 111.31, 116.11, 119.41, 122.17,
127.04, 129.02, 132.31, 136.43, 147.08, 156.10. Mass
spectrum, m/z (Irel, %): 342.17 (25.5) [M]+, 116 (100).
Found, %: C 80.55; H 6.45; N 8.11. C23H22N2O. Cal-
culated, %: C 80.67; H 6.48; N 8.18.
4-[(4-Chlorophenyl)(1H-indol-3-yl)methyl]-N,N-
dimethylaniline (3c). IR spectrum, ν, cm–1: 3410
(NH), 1698 (C=N), 1611, 1575, 1518, 1487, 1456,
1417 (C=C), 1219, 1123 (C–N). 1H NMR spectrum, δ,
ppm: 2.90 s (6H, NCH3), 5.53 s (1H, CH), 6.50 s (1H,
2-H), 7.29–6.66 m (11H, Harom), 7.87 s (1H, Harom),
9.83 s (1H, NH). 13 C NMR spectrum, δC, ppm: 40.52
(NCH3), 54.48 (CH), 111.08, 114.12, 116.28, 120.11,
122.21, 127.71, 130.40, 132.06, 136.03, 140.13,
147.31. Mass spectrum: m/z 360.14/362.14 [M]+.
4-[(4-Hydroxyphenyl)(1H-indol-3-yl)methyl]-
N,N-dimethylaniline (3h). IR spectrum, ν, cm–1: 3408
(NH, OH), 3044, 1681 (C=N), 1586, 1516, 1481, 1450
1
(C=C), 1220 (C–O), 1142 (C–N). H NMR spectrum,
δ, ppm: 2.92 s (6H, NCH3), 5.54 s (1H, CH), 6.56 s
(1H, 2-H), 7.33–6.67 m (12H, Harom), 7.92 s (1H, OH),
9.80 s (1H, NH). 13C NMR spectrum, δC, ppm: 40.45
(NCH3), 55.34 (CH), 111.13, 114.00, 116.15, 119.05,
122.78, 127.07, 129.64, 132.06, 136.31, 147.46,
156.64. Mass spectrum, m/z (Irel, %): 342.17 (25.7)
[M]+, 116 (100). Found, %: C 80.58; H 6.37; N 8.10.
C23H22N2O. Calculated, %: C 80.67; H 6.48; N 8.18.
4-[(2-Chlorophenyl)(1H-indol-3-yl)methyl]-N,N-
dimethylaniline (3d). IR spectrum, ν, cm–1: 3410
(NH), 1694 (C=N), 1611, 1518, 1456, 1442 (C=C),
1
1093, 1036 (C–N). H NMR spectrum, δ, ppm: 2.92 s
(6H, NCH3), 6.00 s (1H, CH), 6.54 s (1H, 2-H), 7.37–
6.72 m (11H, Harom), 7.92 s (1H, Harom), 9.85 s (1H,
NH). 13C NMR spectrum, δC, ppm: 40.38 (NCH3),
50.65 (CH), 111.11, 114.07, 116.31, 120.22, 122.00,
127.13, 130.31, 133.03, 136.44, 143.01, 147.04. Mass
spectrum: m/z 360.14/362.14 [M]+.
4-[(1H-Indol-3-yl)(4-methoxyphenyl)methyl]-
N,N-dimethylaniline (3i). IR spectrum, ν, cm–1: 3408
(NH), 1673 (C=N), 1600, 1510, 1456 (C=C), 1216,
4-[(1H-Indol-3-yl)(3-nitrophenyl)methyl]-N,N-
dimethylaniline (3e). IR spectrum, ν, cm–1: 3411
(NH), 1702 (C=N), 1614 (C=C), 1521 (NO2, asym.),
1
1156 (C–N). H NMR spectrum, δ, ppm: 2.93 s (6H,
NCH3), 5.53 s (1H, CH), 6.56 s (1H, 2-H), 7.33–
6.77 m (11H, Harom), 7.92 s (1H, Harom), 9.86 s (1H,
NH). 13C NMR spectrum, δC, ppm: 40.46 (NCH3),
55.60 (CH, OCH3), 111.08, 114.71, 116.00, 119.07,
122.02, 127.70, 129.99, 132.06, 135.25, 147.01,
158.50. Mass spectrum, m/z (Irel, %): 356.19 (27.8)
[M]+, 116 (100). Found, %: C 80.67; H 6.66; N 7.75.
C24H24N2O. Calculated, %: C 80.87; H 6.79; N 7.86.
1
1349 (NO2, sym.), 1219, 1125 (C–N). H NMR spec-
trum, δ, ppm: 2.94 s (6H, NCH3), 5.68 s (1H, CH),
6.60 s (1H, 2-H), 8.00–6.68 m (11H, Harom), 8.12 s
(1H, Harom), 9.85 s (1H, NH). 13C NMR spectrum, δC,
ppm: 40.50 (NCH3), 54.61 (CH), 111.07, 114.12,
116.01, 118.45, 122.03, 127.34, 130.26, 132.14, 134.71,
144.30, 148.10. Mass spectrum: m/z 371.16 [M]+.
4-[(3,4-Dimethoxyphenyl)(1H-indol-3-yl)-
methyl]-N,N-dimethylaniline (3f). IR spectrum, ν,
cm–1: 3403 (NH), 1671 (C=N), 1599, 1509, 1456
(C=C), 1216, 1156 (C–N). 1H NMR spectrum, δ, ppm:
2.92 s (6H, NCH3), 3.76 s (3H, OCH3), 3.85 s (3H,
OCH3), 5.54 s (1H, CH), 6.56 s (1H, 2-H), 7.33–
6.67 m (10H, Harom), 8.00 s (1H, Harom), 9.87 s (1H,
NH). 13C NMR spectrum, δC, ppm: 40.42 (NCH3),
56.63 (CH, OCH3), 111.07, 114.32, 116.43, 119.87,
122.31, 127.45, 129.00, 132.10, 136.21, 147.08,
150.02. Mass spectrum, m/z (Irel, %): 386.20 (27.9)
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